Process for preparing a micro capsule

ABSTRACT

A process for preparing microcapsules which comprises; dissolving a film-forming polymer in an organic solvent to form a solution, said solvent having a dielectric constant between 10 and 40 and a poor compatibility with liquid paraffins and silicone oils; dispersing a core substance in the solution, to form a first dispersion; dispersing said first dispersion in an encapsulating medium comprising a liquid paraffin or a silicone oil in the form of fine droplets; and evaporating the solvent and the encapsulating medium from the dispersion.

United States Patent 1 Kitajima et a1.

[ 1 Jan. 30, 1973 [54] PROCESS FOR PREPARING A MICRO CAPSULE [75]Inventors: Masao Kitajima, Asaji Kondo, both of Saitama; MasatakaMorishita, Jinnosuke Abe, both of Shizuoka, all of Japan [73] Assignee:Fuji Photo Film Co.,Ltd.,kanagawa-, Toyo Jazo Co., Ltd., Shizuoka, bothof Japan 22 Filed: Feb .3,19 71 211 Appl. No.: 112,394

[30] Foreign Application Priority Data Feb. 3, 1970 Japan ..45/9382 [52]US. Cl ..252/3l6, 96/661, 117/100 A,

[51] Int. Cl ..B01j 13/02, B44d l/02, A61k 9/04 [58] Field of Search.....252/3l6; 117/100 A; 424/33, 424/35 [56] References Cited PrimaryExaminer-Richard D. Lovering Attorney-Sughrue, Rothwell, Mion, Zinn &Macpeak [57] ABSTRACT A process for preparing microcapsules whichcomprises; dissolving a film-forming polymer in an organic solvent toform a solution, said solvent having a dielectric constant between 10and 40 and a poor compatibility with liquid paraffi'ns and siliconeoils; dispersing a core substance in the solution, to form a firstdispersion; dispersing said first dispersion in an encapsulating mediumcomprising a liquid paraffin or a silicone oil in the form of finedroplets; and evaporating the solvent and the encapsulating medium fromthe dispersion.

16 Claims, No Drawings PROCESS FOR PREPARING A MICRO CAPSULE BACKGROUNDOF THE INVENTION 1. Field of the Invention This invention relates to aprocess for preparing microcapsules.

2. Description of the Prior Art Many and varied methods for preparingmicrocapsules are known in the art. For example, encapsulating methodsusing liquid paraffin as a medium are described in US. Pat. Nos.2,379,817 and 2,275,154 and Japanese Pat. Publication No. 3700/61;however, it is impossible to encapsulate a hydrophilic material by thesemethods because gelatin is used as the film-forming material therein.The methods described in US. Pat. Nos. 3,423,489 and 3,361,632 andJapanese Pat. Publication No. 5911/64 cannot be used for encapsulating aheat-sensitive material because heating and cooling operations arerequired therein since only a waxy substance liquified by heat is usedas the filmforming material.

Further, the methods described in Japanese Pat. Publication Nos.11,914/69 and 11,915/69 require special apparatus such as a doubleconcentric cylinder for separating the core substance and thefilm-forming material encapsulating them in liquid paraffin by solventextraction.

It is an object of the present invention to remedy theabove-disadvantages.

It is a further object of the present invention to provide anencapsulating method wherein hydrophilic and heat-sensitive materialscan be easily encapsulated.

It is yet another object of the present invention to provide a method ofencapsulation wherein the encapsulation can be effected using onlysimple apparatus, such as a stirrer.

SUMMARY OF THE INVENTION More particularly, it relates to a process forpreparing microcapsules by dissolving a film-forming polymer in asolvent having a dielectric constant between and 40, wherein the solventhas a poor compatibility with liquid paraffins and silicone oils;dispersing a core substance in the resulting solution; dispersing, inthe form of fine droplets, the resulting dispersion in an encapsulatingmedium comprising a liquid paraffin or a silicone oil; and evaporatingthe solvent and the encapsulating medium.

DESCRIPTION OF PREFERRED EMBODIMENTS In this specification, film-formingpolymer or film-forming material indicates a polymer capable of forminga microcapsule wall. The microcapsules produced by the present processhave a particle diameter of about from 50 microns to 5 mm. The materialused as the core material for the preparation of microcapsules accordingto the present invention is any solid powder insoluble in the solventfor the film-forming polymer or a polymer solution thereof. The watersolubility of the core substance is immaterial, as long as it isinsoluble in the polymer solvent. Thus, the present invention isapplicable to a great many core materials.

The process of the present invention will be generally described below.

the solvent for polymer is evaporated at ordinary temperature orelevated temperature or under reduced pressure while continuing thestirring, the film-wall of polymer is formed and a spherical ornear-spherical microcapsule is obtained.

A specific embodiment of the present process is described below for abetter understanding of the invention, in which an enzyme powder isemployed as the core substance to be micro-encapsulated, an entericcellulose acetate phthalate (hereinafter referred to CAP) is used as thefilm-forming polymer, and a liquid paraffin is used as the encapsulatingmedium.

The enzyme is dispersed in a solution of CAP dissolved in acetone andthe dispersed liquid is then added dropwise into liquid paraffinmaintained at 15 C under stirring to emulsify it to the extent of 0.5 to1.5 mm in oil drop size. When the temperature is raised to 25 to 35 Cwhile continuing the stirring, acetone is evaporated together withliquid paraffin to precipitate a solid film of CAP, and anenzyme-containing CAP capsule of 0.5 to 1.5 mm in size is therebyproduced.

In the above example, acetone and liquid paraffin (i.e., the polymersolvent and encapsulating medium, respectively) are scarcely miscible,since acetone has a dielectric constant of 2.07 and liquid paraffinabout 2. Acetone only scarcely dissolves liquid paraffin and liquidparaffin dissolves acetone in an amount of about only 10 percent.Further, the CAP is soluble in the acetone but insoluble in the liquidparaffin. By this method an enzyme which is unstable to the change ofboth pH and heat and is soluble in water can be microencapsulated.

The combinations of polymer'and solvent, which may be used in thepresent process, are exemplified as follows, with one skilled in the artbeing able to select an appropriate solvent for any film-formingpolymer.

Polymer Solvent Cellulose acetophthalate Acetone Acrylic acid-acrylicacid ester copolymer Acetone-ethanol (l 1 by weight) Shellac EthanolAcetone-ethanol (l l by weight) Acetone-ethanol (l l by weight) 1Acetone or ethanol Ethanol copolymer Acetone or Acetoneethanol (l l byweight Styrene-maleic anhydride copolymer Acetone or Acetoneethanol (1 lby weight) 'CABP Examples of other film-forming polymers are a copolymerof methyl acrylate and methacrylic acid, and a complex of gelatin andalkyl sulfate.

The solvents which may be used in the process of the present inventionand their dielectric constants are as follows:

Methanol 32.6 Ethanol 24.3 lsopropanol 18.7 Butanol l7.l Benzyl alcohol13.1 Ethylene glycol 37.7 Propylene glycol 35.0 Phenol 9.8

Acetone 20.7 Acetic acid 9.7

Acetic acid anhydride 20.7 Nitromethane 35.9 Ethylene diamine 14.2Acetic acid Cellosolve 16 Other solvents having the proper dielectricconstant and which are not compatible with the encapsulating medium areincluded within the scope of the present invention, one skilled in theart being readily able to select such solvents based on the presentdisclosure.

For example, cyclohexane and methylethylketone, etc., cannot be used inthe process of the present invention even though their dielectricconstants are within the range of to 40 because they are very compatiblewith liquid paraffin. The solvent for the polymer is required to be notsoluble or only slightly soluble in liquid paraffin or silicone oil,which is the encapsulating medium; that is, is required to be so-calledpoorly compatible with the encapsulating medium.

In case of using a mixture of solvents, the dielectric constant of themixture may be in the range of 10 to 40, preferably to 35.

In the process of the present invention, although the ratio of coresubstance to film-forming polymer is optional, when 1/5 to 10 parts byweight of the film-forming polymer are used per 1 part by weight of thecore substance, the encapsulating operation can be easily conducted andthe wall-film of the resulting capsule is strong. The amount by weightof the liquid paraffin or silicone oil to be used as the encapsulatingmedium is suitably four to 15 times that of the dispersion liquid of thecore substance in the polymer solution since, if it is too small, thecapsules easily adhere to each other and form lumps, and, if too large,the production and recovering of the capsules are complicated.

A typical example of a liquid paraffin is liquid paraffin itself, and,among No. 1 to No. 4 thereof, No. 4, which is high in viscosity, is easyto use. Further, paraffms identified by the Japanese Pharmacopoeia andhalogenated paraffins can also be employed.

The silicone oil may be, for example, methyl silicone oil, phenylsilicone oil, or methylphenyl silicone oil. The silicone oil chosenpreferably has a viscosity of about 50 to 500 cp at 25 C; however, theutilization thereof is limited because its compatibility with thepolymer solvent is higher than that of liquid paraffin.

The evaporation of the solvent and the encapsulation medium may beconducted at a temperature lower than the boiling points thereof. Inaddition, the temperature may be higher than room temperature (25 C).

The process of the present invention is characterized in that:

1. a water soluble material can be efficiently encapsulated;

2. a material unstable to heat can be encapsulated;

3. as the film-forming polymer, a stomach-soluble polymer which solutesonly in the range of lower pH and an enteric soluble polymer whichsolutes only in the range of higher pH, etc., can be widely utilized;

4. the capsules can be easily arranged in the desired particle sizesince the encapsulating medium is considerably viscous; and

5. the present process is suitable for encapsulating medicines andsubstances having strong reactivity since the encapsulating mediumemployed is the most inert (with respect to solubility, reactivity andtoxicity) among materials known at the present time.

The present invention is more specifically described by the followingexamples, which are intended as illustrative rather than limiting innature:

EXAMPLE 1 Twenty g of corn starch and 20 g of antiphlogistic enzymepowder (Letiquinonase, manufactured by Toyo Jozo Co., Ltd.) weredispersed in a solution of 100 g of cellulose acetate phthalate (100cps, enteric polymer, manufactured by Wako Junyaku Co.) dissolved in 500ml of acetone. On the other hand, as an encapsulating medium, 60 g ofcorn starch was dispersed in a solution of 60 ml of an emulsifier (tradename: Supan manufactured by Kao Atlas Co.) dissolved in 6 liters ofliquid paraffin (JIS No. 4) and cooled to 5 C.

The enzyme dispersion was added to the encapsulating medium understirring to produce finely divided droplets of 0.5 to 1 mm in size. Bycontinuing the stirring while slowly raising the temperature to 25 C for5 hours, acetone was totally evaporated to precipitate out a solid filmof CAP, and the film encapsulated the enzyme and corn starch to producemicrocapsules of 0.5 to 1 mm in size. By washing the liquid paraffinadhered on the capsule wall with benzene and drying, 200 g ofmicrocapsules were obtained.

The microcapsules prepared by the above-described process had aboutpercent of the original enzyme activity (i.e., the protein decompositionactivity in the antiphlogistic enzyme (Letiquinonase) and itsdeactivation were scarcely observed in the microencapsulation process).When these capsules were shaken in an artificial gastric juice (JapanesePharmacopoeia) for 30 minutes and dissolved in an artificial intestinaljuice and the enzyme activity was then measured by the Anson-KnizMethod, it was found that an uncapsulated enzyme was deactivated in theartificial gastric juice (to 0 in activity) while in the capsulatedenzyme, 80 percent of the activity remained protected from the gastricuice.

EXAMPLE 2 Antiphlogistic enzymes, quinonase (manufactured by Toyo JozoCo., Ltd.), Letiquinonase (manufactured by Toyo Jozo Co., Ltd.), andPronase P (manufactured by Kaken Kagaku Co.) were microcapsulated in thesame manner as in the process described in Example 1, and, in this caseby using 700 ml of acetone and by increasing the stirring velocity overthat used in Example 1, and microcapsules of 0.1 0.2 mm in size wereobtained. Comparing the antiphlogistic effect of the above-describedmicroencapsulated enzyme with that of the uncapsulated enzyme, the goodresults obtained are as follows:

That is, when measuring the rate of dropsy control by oraladministration of drugs by anti-serum dropsy controlling action of ratsand rabbits according to Mr. Yamazakis method (Arch, Int Pharmacodyn,Belgium, 166, 387 (1967) or Punchs method (Journal of Japan PharmacologyAssociation 60, 65 (1964) in 50 mg/Kg of enzyme administered, themicroencapsulated quinonase, letiquinonase and pronase P exhibitedremarkable medicinal effects; i.e., a control rate of 48.4, 50.9 and31.3 percent, respectively, while all the corresponding uncapsulatedenzymes exhibited a percent rate. Further, in 100 mg/kg of enzymeadministered, the microencapsulated quinonase, letiquinonase and pronaseP exhibited a control rate of 71.9, 80.5 and 64.2 percent, respectively,while the control rate of the corresponding uncapsulated enzymes were67.5, 69.7 and 49.7 percent, respectively.

' EXAMPLE 3 According to the process described in Example 1, usingpancreatine (manufactured by Mikuni Kagaku Co.) and pig tripsine(manufactured by Novo Industry Co.) as the core substances, therespective microcapsules were obtained. These microencapsules, as theresult of measurement, exhibited remaining activity of 96 percent, forthe pancreatine, and 94.5 percent for the pig tripsine.

EXAMPLE 4 One g of CABP (gastric) cellulose-type polymer (manufacturedby Wako Junyaku Co.) was dissolved in 30 mg of methanol and 4 g ofL-ascorbic acid powder was dispersed therein. 200 ml of silicone oil(trade name: KF 50, methyl phenyl silicone, lOO cp; manufactured byShinetsu Chemical Co.) dispersed with 4 g of lactose was prepared as anencapsulating medium, and the enzyme dispersion liquid was added theretounder stirring at an ordinary temperature to emulsify the same to about200 p. in size.

By continuing the stirring for 2 hours, methanol was evaporated toquantitatively obtain CABP capsules of 200 p. in size which encapsulatedVitamin C. This capsule dissolved in a pH of below 4.

EXAMPLE 5 Five g of powder of toluylene diamine hydrochloride, which isa color developer for color photography, was dispersed in a solution of2.5 g of CAP dissolved in 25 ml of acetone. Two hundred ml of liquidparaffin was added to the above dispersion liquid under stirring at C.The temperature of the system was raised to 30 C and the stirring wascontinued for 2 hours.

A yellow developer capsule of 1 to 3 mm in size was obtained. Thecapsule was easily soluble in an aqueous alkaline solution of above 9 inpH but was insoluble in acidic pH.

EXAMPLE 6 Five g of sodium carbonate powder was dispersed in a solutionof 1.25 g of CABP dissolved in 25 ml of methanol. The above dispersionliquid was suspended in the form of droplets of 0.5 to 1 mm in size in200 ml of fluid paraffin containing 3 g of silica powder. By heating at40 C for L5 hours, methanol was evaporated to obtain gastric capsules ofCABP of 0.5 to

1 mm in size, encapsulating sodium carbonate therein. The capsules areused for the buffering of pH and func tion such that, when the pH islowered to below 4, the wall film dissolves to practically efflutesodium carbonate to thereby raise the pH.

What is claimed is:

1. A process for preparing microcapsules which com- I prises; dissolvinga film-forming polymer which forms a protective microcapsule wall on thecore material in an organic solvent to form a solution, said solventhaving a dielectric constant between 10 and 40 and a poor compatibilitywith liquid paraffins and silicone oils; dispersing a core substance inthe solution to form a first dispersion; dispersing said firstdispersion in an encapsulating medium comprising a liquid paraffin or asilicone oil in the form of fine droplets; and evaporating the solventand the encapsulating medium from the dispersion whereby saidmicrocapsules are formed.

2. The process as claimed in claim 1 wherein said solvent is methanol,ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol,propylene glycol, phenol, acetone, acetic acid, acetic anhydride,nitromethane, ethyl-enediamine, acetic acid Cellosolve or mixturesthereof. 9

3. The process as claimed in claim 1 wherein said polymer is celluloseacetate phthalate, an acrylic acid/acrylic acid ester copolymer,shellac, cellulose acetate-N, N-di-n-butylhydroxypropyl ether, a 2-methyl-5-vinyl-pyridine/methyl acrylate/methacrylic acid copolymer,polyvinyl pyrrolidone, polyvinyl alcohol, a vinylmethylether/maleicanhydride copolymer, a methyl-methacry-late/maleic anhydride copolymer,a styrene/maleic anhydride copolymer, a methyl methacrylate/methacrylicacid copolymer or a complex of gelatin and alkyl sulfate.

4. The process as claimed in claim 1 wherein the dielectric constant ofsaid solvent varies from about 15 to about 35.

5. The process as claimed in claim 1 wherein said fine droplets vary insize from 0.5 to 1.5 mm.

6. The process as claimed in claim 1 wherein from l/5 to 10 parts byweight of said film-forming polymer are employed to each 1 part byweight of said core substance.

7. The process as claimed in claim 1 wherein the encapsulating medium isemployed in an amount of four to 15 times by weight of the firstdispersion.

8. The process as claimed in claim 1 wherein said core substance is anenzyme.

9. The processas claimed in claim 1 wherein said core substance is asolid powder insoluble in said solvent.

10. The process as claimed in claim 1 wherein said microcapsules have adiameter of from 50 microns to 5 millimeters.

11. The process as claimed in claim 1 wherein said silicone oil ismethyl silicone oil, phenyl silicone oil or methylphenyl silicone oil.

12. The process as claimed in claim 1 wherein said silicone oil has aviscosity at 25 C of from 50 to 500 cp.

13. The process as claimed in claim 1, wherein said film-forming polymeris a resinous polymer which is insoluble in the encapsulating medium.

14. The process of claim 1, wherein said solvent is substantiallyimmiscible with liquid paraffins and silicone oils.

15. The process of claim 1, wherein the core substance is insoluble inthe solvent.

16. The process of claim 1, wherein a mixture of so]- vents is used,which mixture has a dielectric constant of from 10 to 40.

1. A process for preparing microcapsules which comprises; dissolving afilm-forming polymer which forms a protective microcapsule wall on thecore material in an organic solvent to form a solution, said solventhaving a dielectric constant between 10 and 40 and a poor compatibilitywith liquid paraffins and silicone oils; dispersing a core substance inthe solution to form a first dispersion; dispersing said firstdispersion in an encapsulating medium comprising a liquid paraffin or asilicone oil in the form of fine droplets; and evaporating the solventand the encapsulating medium from the dispersion whereby saidmicrocapsules are formed.
 2. The process as claimed in claim 1 whereinsaid solvent is methanol, ethanol, isopropanol, butanol, benzyl alcohol,ethylene glycol, propylene glycol, phenol, acetone, acetic acid, aceticanhydride, nitromethane, ethyl-enediamine, acetic acid Cellosolve ormixtures thereof.
 3. The process as claimed in claim 1 wherein saidpolymer is cellulose acetate phthalate, an acrylic acid/acrylic acidester copolymer, shellac, cellulose acetate-N, N-di-n-butylhydroxypropylether, a 2-methyl-5-vinyl-pyridine/methyl acrylate/methacrylic acidcopolymer, polyvinyl pyrrolidone, polyvinyl alcohol, avinylmethylether/maleic anhydride copolymer, amethyl-methacrylate/maleic anhydride copolymer, a styrene/maleicanhydride copolymer, a methyl methacrylate/methacrylic acid copolymer ora complex of gelatin and alkyl sulfate.
 4. The process as claimed inclaim 1 wherein the dielectric constant of said solvent varies fromabout 15 to about
 35. 5. The process as claimed in claim 1 wherein saidfine droplets vary in size from 0.5 to 1.5 mm.
 6. The process as claimedin claim 1 wherein from 1/5 to 10 parts by weight of said film-formingpolymer are employed to each 1 part by weight of said core substance. 7.The process as claimed in claim 1 wherein the encapsulating medium isemployed in an amount of four to 15 times by weight of the firstdispersion.
 8. The process as claimed in claim 1 wherein said coresubstance is an enzyme.
 9. The process as claimed in claim 1 whereinsaid core substance is a solid powder insoluble in said solvent.
 10. Theprocess as claimed in claim 1 wherein said microcapsules have a diameterof from 50 microns to 5 millimeters.
 11. The process as claimed in claim1 wherein said silicone oil is methyl silicone oil, phenyl silicone oilor methylphenyl silicone oil.
 12. The process as claimed in claim 1wherein said silicone oil has a viscosity at 25* C of from 50 to 500 cp.13. The process as claimed in claim 1, wherein said film-forming polymeris a resinous polymer which is insoluble in the encapsulating medium.14. The process of claim 1, wherein said solvent is substantiallyimmiscible with liquid paraffins and silicone oils.
 15. The process ofclaim 1, wherein the core substance is insoluble in the solvent.